Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common form of dementia in the world. Studies report the presence of extracellular amyloid plaques consisting of β-amyloid peptide and intracellular tangles consisting of hyperphosphorylated tau proteins as the histopathological indicators of AD. The process of β-amyloid peptide generation by sequential cleavage of amyloid precursor protein by β-secretase (BACE1) and γ-secretase, followed by its aggregation to form amyloid plaques, is the mechanistic basis of the amyloid hypothesis. Other popular hypotheses related to the pathogenesis of AD include the tau hypothesis and the oxidative stress hypothesis. Various targets of the amyloid cascade are now in prime focus to develop drugs for AD. Many BACE1 inhibitors, β-amyloid aggregation inhibitors, and Aβ clearance strategies using monoclonal antibodies are in various stages of clinical trials. This review provides an in-depth evaluation of the role of BACE1 in disease pathogenesis and also highlights the therapeutic approaches developed to find more potent but less toxic inhibitors for BACE1, particularly emphasizing the natural scaffold as a nontoxic lead for BACE1 inhibition. Cellular targets and signaling cascades involving BACE1 have been highlighted to understand the physiological role of BACE1. This knowledge is extremely crucial to understand the toxicity evaluations for BACE1-targeted therapy. We have particularly highlighted the scope of flavonoids as a new generation of nontoxic BACE1 inhibitory scaffolds. The structure–activity relationship of BACE1 inhibition for this group of compounds has been highlighted to provide a guideline to design more selective highly potent inhibitors. The review aims to provide a holistic overview of BACE1-targeted therapy for AD that paves the way for future drug development.

中文翻译：

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β-分泌酶（BACE1）靶向治疗阿尔茨海默氏病的范围：强调基于类黄酮的天然支架对BACE1的抑制作用

阿尔茨海默氏病（AD）是一种进行性神经退行性疾病，是世界上最常见的痴呆形式。研究报道了由β-淀粉样蛋白肽组成的细胞外淀粉样斑块和由高磷酸化tau蛋白组成的细胞内缠结的存在作为AD的组织病理学指标。通过β-分泌酶（BACE1）和γ-分泌酶顺序切割淀粉样蛋白前体蛋白，然后使其聚集形成淀粉样蛋白斑，生成β-淀粉样蛋白肽的过程是淀粉样蛋白假说的机理基础。与AD的发病机理有关的其他流行的假设包括tau假设和氧化应激假设。淀粉样蛋白级联的各种靶点现在主要集中在开发用于AD的药物上。许多BACE1抑制剂，β-淀粉样蛋白聚集抑制剂，使用单克隆抗体的Aβ和Aβ清除策略处于临床试验的各个阶段。这篇综述提供了对BACE1在疾病发病机理中的作用的深入评估，并重点介绍了开发出的治疗方法，以寻找更有效但毒性较小的BACE1抑制剂，特别是强调天然支架作为BACE1抑制的无毒先导。已经强调了涉及BACE1的细胞靶标和信号传导级联，以了解BACE1的生理作用。这些知识对于了解针对BACE1的疗法的毒性评估至关重要。我们特别强调了类黄酮作为新一代无毒BACE1抑制支架的范围。BACE1抑制物对这组化合物的结构-活性关系得到了强调，为设计更具选择性的高效抑制剂提供了指导。该综述旨在提供针对BACE1的AD疗法的整体综述，为将来的药物开发铺平道路。